1. Field of the Invention
This invention relates to a an improvement in the process for producing a polymer-drug microcapsule pharmaceutical composition wherein the composition comprises a core containing at least one water soluble, hormonally active polypeptide and, optionally, a polymer hydrolysis modifying agent encapsulated in a bioderodable or biodegradable, biocompatible (co)polymer matrix. The improvement comprises a process for extracting volatile solvents entrained in the polymer-drug microcapsule pharmaceutical composition comprising the steps of (1) contacting the polymer-drug microcapsule pharmaceutical composition with a dense, that is, pressurized, gas and (2) then removing the dense gas, and the volatile solvents therein which have been extracted, from the polymer-drug microcapsule composition.
2. Description of Related References
Kent et al., U.S. Pat. No. 4,675,189 issued Jun. 23, 1987, discloses novel sustained release microcapsule compositions comprising water-soluble, hormonally-active polypeptides and, optionally, a polymer hydrolysis modifying agent, encapsulated in a biocompatible, biodegradable polymer.
More particularly, the patent covers a pharmaceutical composition designed for sustained release over a period of at least 1 month of a luteinizing hormone-releasing hormone (LHRH) analog, prepared in microcapsule form, comprising at least one LHRH analog or pharmaceutically acceptable salt thereof in an amount between about 0.01 and 40.0 wt. %, and a poly(lactide-co-glycolide) polymer (PLGA) having a lactic acid:glycolic acid molar ratio of 75:25 to 40:60, the polymer being present in an amount of between about 99.99 and 60.0 wt. %.
The patented pharmaceutical composition contains as the polypeptide component preferably those nona- and deca-peptides that are LHRH analogs and that are disclosed in U.S. Pat. No. 4,234,571.
The patented pharmaceutical composition designed for sustained release of a therapeutically effective amount of polypeptide over an extended period of time comprising the LHRH analog and poly(lactide-co-glycolide) polymer was prepared in microcapsule form according to the method disclosed in Boswell et al., U.S. Pat. No. 3,773,919 issued Nov. 20, 1973.
In brief, the procedure for preparing the patented pharmaceutical composition designed for sustanied release of a hormonally active polypeptide, particularly a LHRH analog, in microcapsule form involves dissolving the polymer in a halogenated hydrocarbon solvent, dispersing an aqueous polypeptide-containing solution in this polymer-solvent solution, and adding some agent which is soluble in the halogenated hydrocarbon solvent but is a non-solvent for the encapsulating excipient. The addition of the non-solvent, called a coacervation agent, causes the polymeric excipient to precipitate out of the halogenated hydrocarbon solvent onto the dispersed polypeptide-containing water droplets, thereby encapsulating the polypeptide. For example, a poly(lactide-co-glycolide) polymer is dissolved in methylene chloride. An aqueous solution of polypeptide is then added with rapid stirring to the solvent-polymer solution forming a water-in-oil emulsion. A second solvent-miscible material such as silicone oil is added with slow stirring to cause the polymeric excipient to precipitate out of the methylene chloride and collect on the water-solvent interface which coats the dispersed water droplets to give microcapsules.
After being formed, the microcapsules are washed and hardened with a suitable organic solvent, washed with water, washed with an aqueous non-ionic surfactant solution, and then dried at room temperature under vacuum. The resulting microcapsules may range in diameter from about 1 to 500 microns, preferably from about 5 to about 200 microns.
Although the pharmaceutical composition containing an LHRH analog, for example, nafarelin in the form of its acetate salt, and the poly(lactide-co-glycolide) polymer in microcapsule form is suitable for its intended pharmaceutical use in treating human patients, the product tends to contain, or retain, some proportion of the solvents in the microcapsule product which are used in the manufacturing process. While the concentration of the residual solvents in the microcapsule product is not believed to render the resulting pharmaceutical composition unsuitable or unsafe for human use, it is preferred to reduce the concentration of the residual solvents in the microcapsule product, such as dichloromethane (methylene chloride) and heptane, in the pharmaceutical composition.
The residual methylene chloride and heptane, which are themselves volatile and readily evaporated in pure liquid form, appear to be entrapped, or entrained, within the spherical polymeric particles of the microcapsule product and thus rendered effectively non-volatile. Exposure of the product to reduced pressure (vacuum), for example, does not result in significant reduction in the levels of either solvent. Because these solvent residues, in particular the dichloromethane residue, are pharmaceutically undesirable, there is a need for a process or method to eliminate or to substantially reduce the amounts of such residual solvents in the microcapsular pharmaceutical composition containing a LHRH analog in combination with a poly(lactide-co-glycolide) polymer while leaving the product otherwise intact.
The use of dense gases and other forms thereof such as supercritical fluids has been known and reported in the purification of polymers by extraction of residual monomer and catalyst and water (Ger. Pat. Pubn. DE 3323940); the extraction of caffeine in the production of caffeine-free coffee extract (U.S. Pat. No. 3,843,824); the purification of hop extract, produced by extracting a hop extract produced by extraction of hops with a liquid organic solvent and contaminated with solvent residue, by extracting with supercritical carbon dioxide (AU Pat. Pubn. 8286745 having priority on Ger. Pat. Appln. DE 3131428); the extraction of an organic material from a solid by the solvent, namely CO.sub.2 gas of supercritical condition, the pressure of the supercritical organic solvent being controlled with variation; and purifying maleic anhydride copolymer with olefins or vinyl aromatics by extraction with gas under supercritical conditions to remove hazardous compounds (Ger. Pat. Pubn. 0258416 having priority on Ger. Pat Appln. DD 300648).